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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Fast-desensitizing P2X(3) receptors of nociceptive dorsol root ganglion (DRG) neurons are thought to mediate pain sensation. Since P2X(3) receptor efficiency is powerfully modulated by desensitization, its underlying properties were studied with patch-clamp recording. 2. On rat cultured DRG neurons, 2 s application of ATP (EC(50)=1.52 microm), ADP (EC(50)=1.1 microm) or alpha,beta-meATP (EC(50)=1.78 microm) produced similar inward currents that fully desensitized, at the same rate, back to baseline. Recovery from desensitization was much slower after ATP and ADP than after alpha,beta-meATP and, in all cases, it had sigmoidal time course. 3. By alternating the application of ATP and alpha,beta-meATP, we observed complete cross-desensitization indicating that these agonists activated the same receptors. This notion was confirmed by the similar antagonism induced by 2', 3'-O-(2,4,6,trinitrophenyl)-adenosine triphosphate (TNP-ATP). 4. Recovery from desensitization elicited by ATP was unexpectedly shaped by transient application of alpha,beta-methylene-adenosine triphosphate (alpha,beta-meATP), and vice versa. Thus, short-lasting, full desensitization produced by alpha,beta-meATP protected receptors from long-lasting desensitization induced by subsequent ATP applications. ATP and ADP had similar properties of recovery from desensitization. 5. Low nm concentrations of alpha,beta-meATP (unable to evoke membrane currents) could speed up recovery from ATP-induced desensitization, while low nm concentrations of ATP enhanced it. Ambient ATP levels were found to be in the pm range (52+/-3 pm). 6. The phenomenon of cross-desensitization and protection was reproduced by rP2X(3) receptors expressed by rat osteoblastic cell 17/2.8 or human embryonic kidney cell 293 cells, indicating P2X(3) receptor specificity. 7. It is suggested that transient application of an agonist that generates rapid recovery from desensitization, is a novel, powerful tool to modulate P2X(3) receptor responsiveness to the natural agonist ATP.
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PMID:Agonist-dependence of recovery from desensitization of P2X(3) receptors provides a novel and sensitive approach for their rapid up or downregulation. 1498 Sep 81

The mechanism of mechanical hyperalgesia in inflammation might involve a 'mechanochemical' process whereby stretch evokes the release of adenosine 5'-triphosphate (ATP) from the damaged tissue that then excites nearby primary sensory nerve terminals. In the present study, phosphorylated extracellular signal-regulated protein kinase (pERK) immunoreactivity was used as a marker indicating functional activation of primary afferent neurons to examine the P2X receptor-mediated noxious response in DRG neurons in a rat model of peripheral inflammation. We found that very few pERK-labeled DRG neurons were detected in normal rats after alpha, beta methylene-ATP (alphabetame-ATP) intraplantar injection. However, a number of DRG neurons were labeled for pERK after alphabetame-ATP injection to the complete Freund's adjuvant (CFA) induced inflamed paw. Seventy-three percent of pERK-labeled DRG neurons co-expressed the P2X3 receptor. After mechanical noxious stimulation to the hind paw of CFA-inflamed rats, we found many more pERK-labeled neurons compared to those in the normal rats. Administration of the P2X3 receptor antagonists, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid or 2'- (or 3')-O-(trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly decreased the mechanical stimulation-evoked pERK labeling in CFA-inflamed rats, but not in normal rats. We also found the recruitment of neurons with myelinated A fibers labeled for pERK in CFA-inflamed rats, which was reversed by P2X3 receptor antagonists. Moreover, TNP-ATP dose dependently reduced the mechanical hypersensitivity of CFA rats. These data suggest that the P2X receptors in primary afferent neurons increase their activity with enhanced sensitivity of the intracellular ERK signaling pathway during inflammation and then contribute to the hypersensitivity to mechanical noxious stimulation in the inflammatory state.
Pain 2004 Apr
PMID:Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. 1503 Sep 45

Previously, it was believed that the lumbar intervertebral disc was innervated segmentally by dorsal root ganglion (DRG) neurons via the sinuvertebral nerves. Recently, it was demonstrated using retrograde tracing methods that the lower disc (L5-L6) is innervated predominantly by upper (L1 and L2) DRG neurons via the sympathetic trunks. Furthermore, we investigated the expression of various pain-related molecules such as calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), P2X(3) receptor and vanniloid receptor 1 (VR1) in DRG neurons innervating the disc using a combination of immunostaining with the retrograde tracing method. This review outlines the distribution and immunocytochemical characterization of DRG neurons innervating the disc. Small nociceptive DRG neurons are classified into nerve growth factor (NGF)-dependent neurons and glial cell line-derived neurotrophic factor (GDNF)-dependent neurons and they can be distinguished by their reactivity for CGRP and IB4, respectively. We found that about half of the neurons innervating the disc were CGRP-immunoreactive (-ir), whilst, only 0.6% of the DRG neurons were IB4-positive, thereby indicating that NGF-dependent neurons are the main subpopulation which transmits and modulates nociceptive information from the disc. In addition, we also demonstrated P2X(3)- and VR1-immunoreactivity in DRG neurons innervating the disc and noted that they were mainly localized in NGF-dependent neurons. It is well known that NGF has sensitizing effects on DRG neurons, with a recent study demonstratng the presence of NGF in the painful intervertebral disc. Therefore, it is suggested that NGF is involved in the generation of discogenic low back pain.
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PMID:Distribution and immunocytochemical characterization of dorsal root ganglion neurons innervating the lumbar intervertebral disc in rats: a review. 1504 45

The irritable bowel syndrome (IBS) is a gastrointestinal motility disorder affecting millions of patients. IBS symptoms include diarrhea, constipation and pain. The etiology of IBS is due partly to changes in the function of nerves supplying the gastrointestinal tract, immune system activation and to psychological factors. P2X receptors are multimeric ATP-gated cation channels expressed by neuronal and non-neuronal cells. Sensory nerve endings in the gastrointestinal tract express P2X receptors. ATP released from gastrointestinal cells activates P2X receptors on sensory nerve endings to stimulate motor reflexes and to transmit nociceptive signals. Antagonists acting at P2X receptors on sensory nerves could attenuate abdominal pain in IBS patients. Primary afferent neurons intrinsic to the gut, and enteric motor- and interneurons express P2X receptors. These neurons participate in motor reflexes. Agonists acting at enteric P2X receptors may enhance gastrointestinal propulsion and secretion, and these drugs could be useful for treating constipation-predominant IBS. Antagonists acting at enteric P2X receptors would decrease propulsion and secretion and they might be useful for treating diarrhea-predominant IBS. Current knowledge of P2X receptor distribution and function in the gut of laboratory animals provides a rational basis for further exploration of the therapeutic potential for drugs acting at P2X receptors in IBS patients. However, more information about P2X receptor distribution and function in the human gastrointestinal tract is needed. Data on the distribution and function of P2X receptors on gastrointestinal immune cells would also provide insights into the therapeutic potential of P2X receptor agents in IBS.
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PMID:Enteric P2X receptors as potential targets for drug treatment of the irritable bowel syndrome. 1505 31

The majority of adenosine triphosphate (ATP)-induced nociceptive transduction and pain has been attributed to ionotropic P2X3 receptors. Metabotropic P2Y receptors, some of which bind pyrimidines as well as purines, have received little attention. Here we have examined the ability of P2Y receptor signaling to evoke action potential firing in functionally identified afferent fibers using the skin nerve preparation from adult mouse. The P2Y2/P2Y4 ligand UTP activated sustained action potential firing in 54% of C fibers in a concentration-dependent manner. The effect was specific for P2Y2/P2Y4 receptors, as the P2Y6 ligand UDP never activated C fibers. In comparison to C fibers, few thinly myelinated A-mechanoreceptors (AM) (12%) were activated by UTP. The majority (70-80%) of the UTP-sensitive C and Adelta fibers responded to the algogen capsaicin with a barrage of action potentials, whereas the UTP-insensitive fibers were largely unresponsive to capsaicin. Furthermore, 86% of the UTP-sensitive C fibers and 100% of the UTP-sensitive AM fibers also responded to the P2X agonist alpha,beta-methylene ATP, indicating that P2Y and P2X receptors are widely co-expressed. Surprisingly, a significant proportion (20-40%) of low threshold slowly and rapidly adapting Abeta fibers were also activated by UTP and alpha,beta-methylene ATP. These data indicate that P2Y receptors on the terminals of capsaicin-sensitive cutaneous sensory neurons effectively evoke nociceptive transmission, and support the hypothesis that UTP may be an endogenous nociceptive messenger. Furthermore, P2Y signaling may contribute to mechanotransduction in low threshold Abeta fibers under normal or pathological conditions.
Pain 2004 May
PMID:The P2Y agonist UTP activates cutaneous afferent fibers. 1508 24

P2X receptors play a role in the transduction of sensory signals like pain. Few studies have been undertaken on altered P2X(3) receptor (P2X3) expression in sensory neurones after peripheral nerve injury. In the present study, we investigated chronological alterations in P2X3 immunoreactivity and its protein content in the trigeminal ganglion after ischaemic insult in the Mongolian gerbil. In the sham-operated group, P2X3-immunoreactive neurones were found abundantly in small- and medium-sized neurones. From 1 day after ischaemic insult, the number of P2X3-immunoreactive neurones decreased significantly. At 5 days after ischaemic insult, P2X3 immunoreactivity was observed in few neurones, but its immunoreactivity was weak. However, the number of cresyl violet-positive neurones was unchanged throughout this period in all groups. These results suggest that transient trigeminal ganglion ischaemia may provoke a decrease of P2X3 expression and its protein content, and that this down-regulation of P2X3 may be related to the altered pain and thermal sensation without being associated with a transient ischaemic insult.
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PMID:Chronological alterations of P2X3 receptor expression in the trigeminal ganglion after ischaemic insult in the Mongolian gerbil. 1523 13

ATP is implicated in peripheral nociception following activation of P2X, and particularly P2X(3) receptors. The present study examined interactions between alphabeta-methylene-ATP (a P2X(3) receptor ligand) and 5-hydroxytryptamine (5-HT), noradrenaline (NA) and histamine, following local administration into the hindpaw, on spontaneous pain behaviors and thermal hyperalgesia in Sprague-Dawley rats. The interaction with NA was further explored using systemic 6-hydroxydopamine (6-OHDA) and locally administered indomethacin. alphabeta-methylene-ATP produced no spontaneous pain behaviors. Coadministration of 5-HT with alphabeta-methylene-ATP mildly augmented flinching behaviors, while histamine had no such effect. Coadministration of NA with alphabeta-methylene-ATP produced a pronounced expression of flinching and biting/licking behaviors. alphabeta-Methylene-ATP, given alone, produced thermal hyperalgesia, and this was markedly augmented by both 5-HT and NA, but not histamine. 6-OHDA (neurotoxin for sympathetic neurons) and indomethacin (cyclooxygenase inhibitor) reduced the augmenting effect of NA on alphabeta-methylene-ATP-induced thermal hyperalgesia, but had no effect on spontaneous pain behaviors produced by the alphabeta-methylene-ATP/NA combination. Effects of alphabeta-methylene-ATP, NA and their combination were also examined in Long Evans and Wistar rats. In both strains, alphabeta-methylene-ATP and NA both individually led to significant intrinsic flinching behaviors, and the effect of their combination was even more pronounced than in Sprague-Dawley rats. These results provide evidence for: (a) a strong enhancement by NA and 5-HT of nociception produced by peripheral P2X receptors in Sprague-Dawley rats, (b) an indirect action of NA, via sympathetic efferents and prostanoids, with thermal hyperalgesia, and (c) a greater expression of spontaneous pain behaviors with alphabeta-methylene-ATP and NA alone, and with their combination, in Wistar and Long Evans rats compared to Sprague-Dawley rats.
Pain 2004 Jul
PMID:Peripheral P2X receptors and nociception: interactions with biogenic amine systems. 1527 55

Platelet-activating factor (PAF) is a potent inflammatory lipid mediator in peripheral tissues. However, its role in mediation of nociception in central nervous system is unknown. In the present study, whether PAF plays some role in pain transduction in the spinal cord was studied in mice. Intrathecal injection of PAF induced tactile pain, tactile allodynia at as low as 10 fg to 1 pg with a peak response at 100 fg, while lyso-PAF was without effect in the range of doses. Tactile allodynia induced by PAF was blocked by a PAF receptor antagonists, TCV-309, WEB 2086 and BN 50739. The expression of PAF receptor mRNA by RT-PCR was observed in DRG and spinal cord in mice. ATP P2X receptor antagonists, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid and 2',3'-O-(2,4,6-trinitrophenyl)adenosine 5-triphosphate, NMDA receptor antagonist, MK 801 and nitric oxide synthetase inhibitor, 7-nitroindazole blocked the PAF-induced tactile allodynia. PAF-induced tactile allodynia and thermal hyperalgesia disappeared in neonatally capsaicin-treated adult mice, while tactile allodynia but not thermal hyperalgesia induced by intrathecally injected alpha,beta-methylene ATP, a P2X receptor agonist, was capsaicin-insensitive. The present study demonstrated that PAF is a potent inducer of tactile allodynia and thermal hyperalgesia at the level of the spinal cord. PAF-evoked tactile allodynia is suggested to be mediated by ATP and the following NMDA and NO cascade through capsaicin-sensitive fiber, different from exogenously injected alpha,beta-methylene ATP which is insensitive to capsaicin treatment.
Pain 2004 Oct
PMID:Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice. 1536 79

Peripherally administered amitriptyline exhibits potential to be a locally active analgesic, while ATP augments peripheral nociception by interacting with P2X(3) receptors on sensory afferents. The present study examined the effects of amitriptyline on flinching and biting/licking behaviours and thermal hyperalgesia produced by alphabeta-methylene-ATP (alphabeta-MeATP), a ligand for P2X(3) receptors, following intraplantar administration into the hindpaw of rats. Coadministration of low doses of amitriptyline (up to 100 nmol) with alphabeta-MeATP augmented thermal hyperalgesia and flinching behaviours. The most active dose of amitriptyline (100 nmol) had no intrinsic effect. Augmentation of alphabeta-MeATP actions appears to be due to increased tissue levels of biogenic amines resulting from inhibition of uptake, as phentolamine (alpha(1)/alpha(2)-adrenergic receptor antagonist) and methysergide (5-hydroxytryptamine or 5-HT(1)/5-HT(2) receptor antagonist) inhibit the augmented flinching produced by alphabeta-MeATP/amitriptyline. When noradrenaline and 5-HT were coadministered with alphabeta-MeATP (both increase the effect of alphabeta-MeATP), amitriptyline had no effect on flinching produced by alphabeta-MeATP/noradrenaline but inhibited flinching produced by alphabeta-MeATP/5-HT. In the presence of low concentrations of formalin (0.5%, 1%; which also increase the effect alphabeta-MeATP), amitriptyline inhibited augmented behaviours. Higher doses of amitriptyline (300-1000 nmol) increased thermal thresholds, suppressed thermal hyperalgesia produced by alphabeta-MeATP, and inhibited flinching produced by alphabeta-MeATP. Collectively, these results indicate that amitriptyline produces complex influences on peripheral pain signaling by P2X receptors. Lower doses augment nociception by alphabeta-MeATP (probably by inhibiting noradrenaline and 5-HT uptake) but inhibit alphabeta-MeATP responses in the presence of inflammatory mediators (perhaps reflecting receptor blocking properties); higher doses uniformly inhibit nociception by alphabeta-MeATP (perhaps reflecting local anesthetic properties).
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PMID:Amitriptyline produces multiple influences on the peripheral enhancement of nociception by P2X receptors. 1538 Oct 49

On nociceptive neurons, one important mechanism to generate pain signals is the activation of P2X(3) receptors, which are membrane proteins gated by extracellular ATP. In the presence of the agonist, P2X(3) receptors rapidly desensitize and then recover slowly. One unique property of P2X(3) receptors is the recovery acceleration by extracellular Ca(2+) that can play the role of the gain-setter of receptor function only when P2X(3) receptors are desensitized. To study negatively charged sites potentially responsible for this action of Ca(2+), we mutated 15 non-conserved aspartate or glutamate residues in the P2X(3) receptor ectodomain with alanine and expressed such mutated receptors in human embryonic kidney cells studied with patch clamping. Unlike most mutants, D266A (P2X(3) receptor numbering) desensitized very slowly, indicating that this residue is important for generating desensitization. Recovery appeared structurally distinct from desensitization because E111A and D266A had a much faster recovery and D220A and D289A had a much slower one despite their standard desensitization. Furthermore, E161A, E187A, or E270A mutants showed lessened sensitivity to the action of extracellular Ca(2+), suggesting that these determinants were important for the effect of this cation on desensitization recovery. This study is the first report identifying several negative residues in the P2X(3) receptor ectodomain differentially contributing to the general process of receptor desensitization. At least one residue was important to enable the development of rapid desensitization, whereas others controlled recovery from it or the facilitating action of Ca(2+). Thus, these findings outline diverse potential molecular targets to modulate P2X(3) receptor function in relation to its functional state.
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PMID:Identification of negative residues in the P2X3 ATP receptor ectodomain as structural determinants for desensitization and the Ca2+-sensing modulatory sites. 1547 63


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